Abstract

The recently identified histamine receptor, H₄, was shown to be primarily expressed on leukocytes and has been implicated in the activation of lymphocytes, eosinophils, and mast cells in vitro. Its function in vivo, however, has not yet been characterized. We present evidence for a critical role of H₄ receptor in the mast cell-dependent recruitment of neutrophils. Mice injected with zymosan into the pleural cavity developed massive neutrophilia within hours after challenge. Neutrophilia was dose-dependently reduced when mice were pretreated with thioperamide, a known H_3/4 receptor antagonist, whereas H₁ and H₂ receptor antagonists lacked efficacy. Similarly, a 70 to 80% reduction in neutrophils in the pleural cavity compared with wild-type animals was noted in mice lacking mast cells (W/W^v mice); mice deficient in MyD88 (MyD88^–/–); a critical component of the signaling cascade of the major receptor for zymosan, toll-like receptor 2 (TLR2); or in mice pretreated with a functionally antagonistic anti-TLR2 antibody. The residual 20% neutrophil infiltration seen in mast cell-deficient and MyD88^–/– mice was not further reduced by thioperamide. Neutrophilia was completely restored by transferring wild-type bone marrow-derived mast cells into MyD88^–/– or W/W^v mice. Interestingly, when neutrophilia was evoked by carrageenan injection, mast cell depletion and thioperamide had no effect. Various inflammatory mediators were detectable in the pleural cavity of zymosan-challenged mice. Upon pretreatment with thioperamide, reduced levels of the neutrophil chemattractant leukotriene B₄ were observed, providing a mechanistic explanation for the prevention of neutrophilia by H₄ receptor antagonism.